Tandem quadrupole mass spectrometer

ABSTRACT

A dwell time calculation table ( 51   a ) showing a correspondence relation between a CID gas pressure inside a collision cell ( 31 ) and a dwell time for data collection is stored in a processing condition parameter memory ( 51 ) of a controller ( 50 ). In the table ( 51   a ), as the CID gas pressure becomes higher, the dwell time becomes longer. When an instruction to execute an MRM measurement mode is given, the controller ( 50 ) determines the dwell time in accordance with the currently set CID gas pressure, and controls a data collector ( 41 ) to accumulate detection signals from an ion detector ( 34 ) during the determined dwell time and obtain the accumulated value. If the CID gas pressure inside the collision cell ( 31 ) is high, a decrease in ion speed becomes remarkable, and the rising of the ion intensity becomes slow. However, if the dwell time becomes long, influences of the slow rising on the accumulated value are relatively reduced, and the accuracy of the accumulated value is enhanced. Accordingly, the quantitative accuracy can be enhanced.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage of International Application No.PCT/JP2012/080327 filed Nov. 22, 2012, the contents of all of which areincorporated herein by reference in their entirety.

TECHNICAL FIELD

The present invention relates to a tandem quadrupole mass spectrometerwhich dissociates ions having a specific mass-to-charge ratio m/zthrough collision-induced dissociation (CID) or the like and performs amass spectrometric analysis on product ions (fragment ions) producedthrough the dissociation.

BACKGROUND ART

A method called an MS/MS analysis (also called a tandem analysis) isknown as one of the mass spectrometric analysis techniques foridentification and structural analyses of substances having largemolecular weights. A tandem quadrupole mass spectrometer (also called atriple quadrupole mass spectrometer) having a relatively simple andinexpensive structure is one of the widely used mass spectrometerscapable of performing the MS/MS analysis.

As disclosed in Patent Literature 1, generally in the tandem quadrupolemass spectrometer, quadrupole mass filters are provided respectivelybefore and after (i.e. at the front stage and rear stage of) a collisioncell for dissociating ions, where precursor ions are selected by thefront-stage quadrupole mass filter from among a variety of ionsoriginating from a target compound, and product ions are separated bythe rear-stage quadrupole mass filter in accordance with theirmass-to-charge-ratios. The collision cell has a box-like, relativelytight-sealed structure, and a CID gas such as argon and nitrogen isintroduced into the collision cell. The precursor ions selected by thefront-stage quadrupole mass filter are introduced into the collisioncell endowed with appropriate collision energy, and collide with the CIDgas inside the collision cell. As a result, collision-induceddissociation occurs, and the product ions are produced.

The dissociation efficiency of ions inside the collision cell depends onthe amount of collision energy of the ions, the CID gas pressure insidethe collision cell, and the like. Hence, the detection sensitivity ofthe product ions that have passed through the rear-stage quadrupole massfilter also depends on the amount of collision energy and the CID gaspressure.

In the tandem quadrupole mass spectrometer, a measurement in a multiplereaction monitoring (MRM) mode is performed in many cases, in order toperform quantitative determination on a known compound with highaccuracy and sensitivity. In the MRM measurement mode, for both thefront-stage and rear-stage quadrupole mass filters, themass-to-charge-ratios of the ions that pass through the filters arefixed. Hence, in conventional tandem quadrupole mass spectrometers, theCID gas pressure inside the collision cell is set to a value (normally,at several mTorr) that is determined in advance by a manufacturer suchthat the detection sensitivity is as high as possible in the MRMmeasurement mode. Of course, the CID gas supply pressure can be manuallyadjusted by a user, whereby a measurement can be performed with highersensitivity than that under such a preset condition as described above,with regard to, for example, a specific compound.

In general, as the CID gas pressure inside the collision cell becomeshigher, ions become more likely to contact the CID gas, and hence thedissociation efficiency of the ions becomes higher. However, the kineticenergy of the ions is attenuated by the collision with the CID gas, andhence the flight speed of the ions as a whole decreases. In the case ofthe MRM measurement mode, dissociation of precursor ions having a givenmass-to-charge-ratio and selection and detection of product ions havinga given mass-to-charge-ratio are performed for a certain amount of time,and hence the decrease in ion flight speed in the collision cell asdescribed above is considered to have relatively small influences on theion intensity. However, in actuality, even in the MRM measurement mode,if the CID gas pressure is raised, the ion intensity obviously decreasescompared with the case where the CID gas pressure is low. As a result,there arises a problem that a sufficiently high peak cannot be obtainedon a mass chromatogram at a mass-to-charge-ratio corresponding to atarget compound and that the quantitative accuracy thus decreases.

Moreover, a wide variety of measurement modes other than the MRMmeasurement mode described above are prepared for the tandem quadrupolemass spectrometer. Examples of the other measurement modes include:measurement modes in which both the front-stage and rear-stagequadrupole mass filters perform ion selection (a precursor ion scanmeasurement mode, a product ion scan measurement mode, a neutral lossscan measurement mode, and the like); and measurement modes in which oneof the front-stage and rear-stage quadrupole mass filters does notperform ion selection (namely, all ions pass through the filter intact)while the other of the front-stage and rear-stage quadrupole massfilters performs a mass scan. In general, in all measurement modesexcept for measurement modes in which CID is not performed inside thecollision cell, the CID gas pressure inside the collision cell is set toa value that is determined in advance by the manufacturer such that thedetection sensitivity is as high as possible in the MRM measurementmode, as described above.

However, under such control, in the precursor ion scan measurement modeand the neutral loss scan measurement mode in which the front-stagequadrupole mass filter performs a scan over a predeterminedmass-to-charge-ratio range, a mass-to-charge-ratio deviation of a targetion peak on a mass spectrum (MS/MS spectrum), which results from thedecrease in ion flight speed inside the collision cell as describedabove, tends to become large. The degree of the decrease in ion flightspeed inside the collision cell also depends on the ion size (whichnormally corresponds to the mass-to-charge-ratio). Hence, the degree ofthe mass-to-charge-ratio deviation on the mass spectrum is not alwaysconstant, and it is not easy to obtain the amount of deviation andcorrect the deviation. Moreover, variation in flight speed increaseseven among ions having the same mass-to-charge-ratio, and this causes aproblem that the peak width becomes large on the mass spectrum,resulting in a decrease in mass resolution.

Furthermore, the MRM measurement mode is used in many cases for asimultaneous multicomponent analysis by a liquid chromatograph massspectrometer or a gas chromatograph mass spectrometer, and the number ofpairs of a precursor ion and a product ion to be detected simultaneouslyin parallel increases if the number of measurement target compoundsincreases. To deal with this, it is necessary to make high-speedswitching of the mass-to-charge-ratio of ions that are allowed to passthrough the front-stage quadrupole mass filter. As a result, suchinfluences of the decrease in ion intensity as described above becomefurther remarkable. On the other hand, even though the number ofmeasurement target compounds is decreased in order to perform ameasurement on each compound with high sensitivity, the improvement insensitivity is limited.

CITATION LIST Patent Literature

[Patent Literature 1] WO 2009/095958 A

SUMMARY OF INVENTION Technical Problem

The present invention, which has been made in order to solve theabove-mentioned problems, has a first object to provide a tandemquadrupole mass spectrometer capable of minimizing a decrease insensitivity caused by raising a CID gas pressure inside a collision cellin an MRM measurement or the like.

The present invention further has a second object to provide a tandemquadrupole mass spectrometer capable of reducing a mass-to-charge-ratiodeviation on a mass spectrum obtained in a precursor ion scanmeasurement, a neutral loss scan measurement, or the like.

The present invention further has a third object to provide a tandemquadrupole mass spectrometer capable of performing an appropriatemeasurement suited to intended measurement conditions and intendedmeasurement purpose in the case, for example, where a high-speedmeasurement is necessary because the number of measurement targetcompounds is large in a simultaneous multicomponent analysis or where ahigh-sensitivity measurement is desired to be performed because thenumber of measurement target compounds is relatively small.

Solution to Problem

A first specific form of the present invention, which has been made inorder to achieve the above-mentioned first object, provides a tandemquadrupole mass spectrometer including: a front-stage quadrupole massfilter for selecting, as precursor ions, ions having a specificmass-to-charge-ratio from among a variety of ions; a collision cell forcausing the precursor ions to collide with a predetermined gas todissociate the ions; a rear-stage quadrupole mass filter for selectingions having a specific mass-to-charge-ratio from among a variety ofproduct ions produced through the dissociation; and a detector fordetecting the selected product ions, the tandem quadrupole massspectrometer further including:

a) a gas adjuster for adjusting a supply pressure or a supply flow rateof a gas supplied to an inside of the collision cell such that a gaspressure inside the collision cell is in a desired state; and

b) a controller for changing a length of a dwell time in accordance withthe gas supply pressure or the gas supply flow rate set by the gasadjuster or a target gas pressure when a measurement in a multiplereaction monitoring measurement mode is performed, the dwell time beinga period of time to take in signals obtained by the detector with regardto precursor ions and product ions originating from one compound.

A second specific form of the present invention, which has been made inorder to achieve the above-mentioned first object, provides a tandemquadrupole mass spectrometer including: a front-stage quadrupole massfilter for selecting, as precursor ions, ions having a specificmass-to-charge-ratio from among a variety of ions; a collision cell forcausing the precursor ions to collide with a predetermined gas todissociate the ions; a rear-stage quadrupole mass filter for selectingions having a specific mass-to-charge-ratio from among a variety ofproduct ions produced through the dissociation; and a detector fordetecting the selected product ions, the tandem quadrupole massspectrometer further including:

a) a gas adjuster for adjusting a supply pressure or a supply flow rateof a gas supplied to an inside of the collision cell such that a gaspressure inside the collision cell is in a desired state; and

b) a controller for changing a length of a settling time in accordancewith the gas supply pressure or the gas supply flow rate set by the gasadjuster or a target gas pressure when a measurement in a multiplereaction monitoring (MRM) measurement mode is performed, the settlingtime being an allowance time necessary for settling of a voltage appliedto the front-stage and/or rear-stage quadrupole mass filter when theapplied voltage is changed in order to perform a measurement with atleast one of precursor ions and product ions being different, aftersignals obtained by the detector with regard to precursor ions andproduct ions originating from one compound are taken in.

In the tandem quadrupole mass spectrometer according to each of thefirst and second specific forms, examples of the detector include adetector including a multi-stage dynode secondary electron multiplierand a detector including a conversion dynode, a fluorescent material,and a photoelectron multiplier in combination. Detection signalsobtained by the detector thus configured are accumulated or averagedduring the dwell time, whereby measurement data on a given point isobtained. Moreover, in the case where ions originating from a pluralityof compounds need to be measured simultaneously in parallel in the MRMmeasurement mode, the voltage applied to the front-stage and/orrear-stage quadrupole mass filter is changed at the time of switching ofmeasurement target ions, and hence the settling time is set such thatdata acquisition is suspended until the applied voltage settles.

In the first specific form, the controller changes the dwell time inaccordance with the gas supply pressure or the gas supply flow rate setby the gas adjuster or the target gas pressure. In the second specificform, the controller changes not the dwell time but the settling time inaccordance with the gas supply pressure or the gas supply flow rate setby the gas adjuster or the target gas pressure. More specifically, thecontroller lengthens the dwell time or the settling time in the casewhere the gas supply pressure, the gas supply flow rate, or the targetgas pressure is high or large, namely, in the case where ions are morelikely to contact the gas inside the collision cell, compared with thecase where the gas supply pressure, the gas supply flow rate, or thetarget gas pressure is not high or large. In the case where ions aremore likely to contact the gas inside the collision cell, the degree ofa decrease in ion flight speed becomes high, and the time delay untilions reach the detector becomes larger. As a result, if the lengths ofboth the settling time and the dwell time are not changed, dataacquisition is unfavorably restarted before the ion intensitysufficiently rises after the voltage applied to the front-stage and/orrear-stage quadrupole mass filter is changed. If the insufficientlyrising ion intensity as described above is included in the accumulatedvalue, the accuracy and the sensitivity of the accumulated value becomerelatively low. This tendency becomes more remarkable as the CID gaspressure inside the collision cell becomes higher.

In the tandem quadrupole mass spectrometer according to the firstspecific form, the dwell time is lengthened in the case where the gaspressure inside the collision cell is high and where the rising of theion intensity is slow. Hence, even if the rising of the ion intensity isinsufficient as described above, the ion intensity has smallerinfluences on the accumulated value, and the accuracy and thesensitivity of the accumulated value are enhanced. Moreover, in thetandem quadrupole mass spectrometer according to the second specificform, in the case where the gas pressure inside the collision cell ishigh and where the rising of the ion intensity is slow, the settlingtime is lengthened, namely, the start timing of data collection isdelayed. Hence, even if the rising of the ion intensity is insufficient,the ion intensity has smaller influences on the accumulated value, andthe accuracy and the sensitivity of the accumulated value are enhanced.In any case, the accuracy and the sensitivity of the signal intensityfor each compound in the MRM measurement mode are enhanced, and theaccuracy of an area value of a peak on a mass chromatogram is enhanced,whereby the quantitative accuracy is increased.

A third specific form of the present invention, which has been made inorder to achieve the above-mentioned second object, provides a tandemquadrupole mass spectrometer including: a front-stage quadrupole massfilter for selecting, as precursor ions, ions having a specificmass-to-charge-ratio from among a variety of ions; a collision cell forcausing the precursor ions to collide with a predetermined gas todissociate the ions; a rear-stage quadrupole mass filter for selectingions having a specific mass-to-charge-ratio from among a variety ofproduct ions produced through the dissociation; and a detector fordetecting the selected product ions, the tandem quadrupole massspectrometer further including:

a) a mode setter for enabling a user to set a measurement mode to beexecuted;

b) a gas supplier for supplying the predetermined gas to an inside ofthe collision cell; and

c) a controller for controlling the gas supplier such that a CID gaspressure inside the collision cell is changed in accordance with themeasurement mode set by the mode setter.

In the tandem quadrupole mass spectrometer according to the thirdspecific form, the controller controls the gas supplier to switch theCID gas pressure inside the collision cell in accordance with the kindof measurement mode to be executed. Specifically, in the case where adecrease in ion speed inside the collision cell becomes significant, theCID gas pressure is lowered such that influences of the decrease in ionspeed relatively lower.

For example, the controller may lower the CID gas pressure inside thecollision cell in a case where the set measurement mode is a measurementmode in which the front-stage quadrupole mass filter performs a massscan and ions are dissociated inside the collision cell, compared with acase where the set measurement mode is a measurement mode in which thefront-stage quadrupole mass filter does not perform a mass scan. Here,the measurement mode in which the front-stage quadrupole mass filterperforms the mass scan and the ions are dissociated inside the collisioncell includes: a precursor ion scan measurement mode; a neutral lossscan measurement mode; and a measurement mode in which only thefront-stage quadrupole mass filter performs the mass scan while therear-stage quadrupole mass filter does not perform ion selectionaccording to a mass-to-charge-ratio.

In the above-mentioned measurement modes, the mass-to-charge-ratio ofprecursor ions introduced into the collision cell changes so as toincrease or decrease with the lapse of time, and hence the ion passagetime inside the collision cell becomes long. In particular, if adifference in ion passage time becomes large depending on amass-to-charge-ratio, a decrease in mass accuracy of a mass spectrumbecomes remarkable. In view of this, in the tandem quadrupole massspectrometer according to the third specific form, when thesemeasurement modes are executed, the CID gas pressure inside thecollision cell becomes relatively low, and the ion passage time insidethe collision cell becomes short. Hence, a mass-to-charge-ratiodeviation can be reduced, and the mass accuracy of a mass spectrum canbe secured.

Moreover, in order to achieve the above-mentioned third object, in thetandem quadrupole mass spectrometer according to the third specificform, at least a high-speed mode in which greater importance is placedon a measurement speed than on a detection sensitivity and ahigh-sensitivity mode in which greater importance is placed on thedetection sensitivity than on the measurement speed may be prepared fora multiple reaction monitoring (MRM) measurement mode, as measurementmodes selectable by the mode setter, and the controller may lower theCID gas pressure inside the collision cell in a case where the setmeasurement mode is the high-speed mode of the MRM measurement mode,compared with a case where the set measurement mode is thehigh-sensitivity mode of the MRM measurement mode.

Here, the high-speed mode is a mode that is used in an MRM measurementin the case where the number of mass-to-charge-ratio pairs of aprecursor ion and a product ion to be measured simultaneously inparallel is large, specifically, in the case where the number ofmeasurement target compounds is specially large in a simultaneousmulticomponent analysis or where the linear speed of a mobile phase in aliquid chromatograph or a gas chromatogram connected in the front stageof the mass spectrometer is high. On the other hand, thehigh-sensitivity mode is a mode that is used in the case where thenumber of kinds of compounds contained in a sample is small and wherehigh-accuracy quantitative determination is desired to be performed oneach compound.

In the case where the high-speed mode is set, the CID gas pressureinside the collision cell is relatively lowered. Hence, the ion passagetime inside the collision cell can be suppressed to be short, and, forexample, the following problem can be avoided. That is, when a production produced by dissociating a given precursor ion tries to pass throughthe rear-stage quadrupole mass filter, the mass-to-charge-ratio of ionsthat are allowed to pass through this mass filter is unfavorably changedto the mass-to-charge-ratio of product ions that are not paired with thegiven precursor ion. Consequently, even in the case where the timeallotted to each mass-to-charge-ratio pair (each channel to be describedlater) of a precursor ion and a product ion is short, a product ionproduced from a target precursor ion can be reliably detected. In thiscase, however, the ion dissociation efficiency inside the collision cellis relatively low, and hence an improvement in detection sensitivityitself is difficult.

In the case where the high-sensitivity mode is set, the CID gas pressureinside the collision cell is relatively raised, and hence the iondissociation efficiency inside the collision cell becomes high. In thiscase, although the ion passage time inside the collision cell is long, ahigh-speed measurement is not required, and hence the voltage applied tothe rear-stage quadrupole mass filter can be maintained until delayedproduct ions completely finish passing through this mass filter.Consequently, a sufficient number of ions can reach the detector, andhigh detection sensitivity can be achieved.

In this way, measurements respectively suitable for both the case wheregreater importance is placed on high speed and the case where greaterimportance is placed on high detection sensitivity can be performed inthe MRM measurement mode.

Advantageous Effects of Invention

In the tandem quadrupole mass spectrometer according to each of thefirst and second specific forms of the present invention, even in thecase where the CID gas pressure inside the collision cell is raised inthe MRM measurement, a decrease in detection sensitivity can beminimized, and the accuracy of an area value of a peak originating froma target compound on a mass chromatogram can be enhanced, whereby highquantitative accuracy can be achieved.

Moreover, in the tandem quadrupole mass spectrometer according to thethird specific form of the present invention, if the CID gas pressure ischanged in accordance with measurement modes such as the precursor ionscan measurement mode and the neutral loss scan measurement mode, amass-to-charge-ratio deviation on a mass spectrum created in each ofthese scan measurement modes can be reduced. Furthermore, in the tandemquadrupole mass spectrometer according to the third specific form of thepresent invention, if the CID gas pressure is changed in accordance withmeasurement modes such as the high-speed mode and the high-sensitivitymode of the MRM measurement, measurements respectively suitable for boththe case where greater importance is placed on high speed and the casewhere greater importance is placed on high detection sensitivity can beperformed.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a schematic configuration diagram of a main part of a firstembodiment of an LC/MS/MS including a tandem quadrupole massspectrometer according to the present invention.

FIG. 2 is a diagram for describing acquisition timing of data in an MRMmeasurement mode and a mass chromatogram based on the data.

FIG. 3A and FIG. 3B are schematic waveform diagrams for describing anexample characteristic data collecting operation by the LC/MS/MS in thefirst embodiment.

FIG. 4A and FIG. 4B are schematic waveform diagrams for describinganother example characteristic data collecting operation by the LC/MS/MSin the present embodiment.

FIG. 5 is a waveform diagram showing actual measurement results of anion signal response time under conditions of different CID gaspressures.

FIG. 6 is a diagram showing actual measurement results of a relationbetween a dwell time and a signal intensity value (accumulated value)under conditions of different CID gas pressures.

FIG. 7 is a schematic configuration diagram of a main part of a secondembodiment of an LC/MS/MS including a tandem quadrupole massspectrometer according to the present invention.

DESCRIPTION OF EMBODIMENTS

Hereinafter, a first embodiment of a liquid chromatograph tandemquadrupole mass spectrometer (hereinafter, called a “LC/MS/MS”)including a tandem quadrupole mass spectrometer according to the presentinvention is described with reference to the attached drawings.

In the LC/MS/MS of the first embodiment, a liquid chromatograph unit 10includes: a mobile phase container 11 for holding a mobile phase; a pump12 for drawing and supplying the mobile phase at a constant flow rate;an injector 13 for injecting a predetermined amount of prepared sampleinto the mobile phase; and a column 14 for temporally separating avariety of compounds contained in the sample. The pump 12 draws themobile phase from the mobile phase container 11 and supplies the drawnmobile phase into the column 14 at a constant flow rate. When apredetermined amount of sample liquid is introduced from the injector 13into the mobile phase, the sample is carried by the mobile phase andintroduced into the column 14. While passing through the column 14, thevariety of compounds in the sample are temporally separated, to beeventually eluted from the outlet of the column 14 and introduced into amass spectrometer 20.

The mass spectrometer 20 has the configuration of a multi-stagedifferential pumping system including an ionization chamber 21maintained at approximately atmospheric pressure and a high-vacuumanalysis chamber 24 evacuated by a high-performance vacuum pump (notshown), between which first and second intermediate vacuum chambers 22and 23 each having a degree of vacuum increased in a stepwise manner areprovided. The ionization chamber 21 has an electrospray ionization probe25 for spraying sample solution while electrically charging thissolution. The ionization chamber 21 communicates with the firstintermediate vacuum chamber 22 in the next stage through a thin heatedcapillary 26. The first and second intermediate vacuum chambers 22 and23 are separated by a skimmer 28 having a small hole at its apex. Ionguides 27 and 29 for transporting ions to the subsequent stage whileconverging the ions are provided in the first and second intermediatevacuum chambers 22 and 23, respectively. The analysis chamber 24contains a collision cell 31 including a multi-pole ion guide 32, afront-stage quadrupole mass filter 30 for separating ions according totheir mass-to-charge ratios and a rear-stage quadrupole mass filter 33for similarly separating ions according to their mass-to-charge ratiosbeing provided before and after the collision cell 31. An ion detector34 is also provided in the analysis chamber 24. A CID gas supplier 35supplies a CID gas such as argon or nitrogen into the collision cell 31.A power source 36 applies predetermined voltages to the electrosprayionization probe 25, the ion guides 27, 29, and 32, the quadrupole massfilters 30 and 33, and other components, respectively.

In the mass spectrometer 20, when the eluate from the column 14 reachesthe electrospray ionization probe 25, the eluate is sprayed while beingsupplied with electric charges from the tip of the probe 25. Theelectrically charged droplets thus formed by the spraying process areprogressively broken into smaller sizes by an electrostatic force due tothe supplied electric charges. During this process, the solvent isvaporized, and ions originating from the compounds are ejected. The ionsthus produced are sent through the heated capillary 26 into the firstintermediate vacuum chamber 22, where the ions are converged by the ionguide 27 and sent through the small hole at the apex of the skimmer 28into the second intermediate vacuum chamber 23. In this chamber, theions originating from the compounds are converged by the ion guide 29and sent into the analysis chamber 24, where the ions are introducedinto the space extending along the longitudinal axis of the front-stagequadrupole mass filter 30. It should be naturally understood that theionization method is not limited to the electrospray ionization butother methods may be used, such as atmospheric pressure chemicalionization or atmospheric pressure photoionization.

When an MS/MS analysis is performed in the mass spectrometer 20, apredetermined voltage (composed of a high-frequency voltage and a DCvoltage superposed on each other) is applied from the power source 36 toeach of the rod electrodes of the front-stage quadrupole mass filter 30and the rear-stage quadrupole mass filter 33, while the CID gas iscontinuously or intermittently supplied from the CID gas supplier 35into the collision cell 31. Among the variety of ions sent into thefront-stage quadrupole mass filter 30, only ions having a specificmass-to-charge ratio corresponding to the voltage applied to each rodelectrode of the front-stage quadrupole mass filter 30 are allowed topass through this filter 30 and be introduced into the collision cell 31as precursor ions. In the collision cell 31, the precursor ions collidewith the CID gas and are thus dissociated, so that a variety of productions are produced. The variety of produced product ions are introducedinto the rear-stage quadrupole mass filter 33, where only product ionshaving a specific mass-to-charge ratio corresponding to the voltageapplied to each rod electrode of the rear-stage quadrupole mass filter33 are allowed to pass through this filter 33, to eventually reach andbe detected by the ion detector 34. The ion detector 34 is apulse-counting detector, and outputs pulse signals whose numbercorresponds to the number of incident ions, as detection signals.

A data processor 40 includes functional blocks such as a data collector41, a data memory 42, a graph creator 43, and a quantitative analyzer44. A controller 50 to which an input unit 52 and a display 53 areconnected controls the operations of the pump 12 and the injector 13 inthe liquid chromatograph unit 10 as well as those of the power source 36and the CID gas supplier 35 in the mass spectrometer 20. At least partof the functions of the controller 50 and the data processor 40 can berealized by installing a dedicated controlling and processing softwareprogram on a personal computer provided as hardware resources andexecuting this program on the computer.

When a quantitative analysis is performed by the LC/MS/MS configured asdescribed above, an MRM measurement mode in which each of thefront-stage quadrupole mass filter 30 and the rear-stage quadrupole massfilter 33 allows only ions having a predetermined mass-to-charge-ratioto pass through the filter is used in many cases. Accordingly,description is given below of the case where a specific product ioncorresponding to a specific precursor ion originating from a targetcompound is detected in the MRM measurement mode. In general, the MRMmeasurement can be performed with a plurality of channels being set, anda mass-to-charge-ratio pair of a precursor ion and a product ion isdefined for each of the channels.

FIG. 2 is a diagram for describing acquisition timing of data and a masschromatogram based on the data in the case where the MRM measurement ofthree channels is performed. For each channel, in order to performquantitative determination on a given compound, the signal intensity ismeasured for precursor ions and product ions each having amass-to-charge-ratio characteristic of the given compound. As shown inFIG. 2, the measurement is performed once for each of the plurality ofchannels in one measurement cycle having a time length of a loop timeTL. Moreover, the product ions originating from each compound aredetected during a dwell time Td. A break time Ts between the dwell timeTd for one compound (for example, a compound a) and the dwell time Tdfor another compound (for example, a compound b) is a settling time setas an allowance time necessary for settling of the voltage applied toeach of the quadrupole mass filters 30 and 33 when the applied voltageis changed in order to change the mass-to-charge-ratio of ions that areallowed to pass through each filter.

The data collector 41 in the data processor 40 has a function ofcounting pulse signals sent from the ion detector 34. As describedabove, during a period of the settling time Ts, themass-to-charge-ratios of ions that pass through the quadrupole massfilters 30 and 33 are not secured. Hence, the data collector 41 discardspulse signals inputted during the settling time Ts without counting thesame, accumulates the number of pulse signals inputted during the dwelltime Td, and converts the accumulation result into digital dataindicating the number of ions that reach the ion detector 34.Accordingly, as shown in FIG. 2, data corresponding to, for example, thecompound a is obtained as D₁, D₂, . . . for each loop time TL. Pieces ofdata corresponding to the other compounds b and c are similarlyobtained, and the obtained pieces of data are stored into the datamemory 42.

The graph creator 43 creates, for example, a mass chromatogram at aspecific mass-to-charge-ratio, based on the data stored in the datamemory 42, and displays the mass chromatogram on the screen of thedisplay 53 through, for example, the controller 50. Basically, as shownin FIG. 2, the graph creator 43 can create the mass chromatogram byplotting the pieces of data D₁, D₂, . . . that are sequentially obtainedat intervals of the loop time TL. The quantitative analyzer 44 detects apeak near the retention time of a target compound on the masschromatogram, and calculates the area of the peak. Then, with referenceto a standard curve that is created in advance based on measurementresults of a sample containing compounds each having a knownconcentration, the quantitative analyzer 44 obtains a concentration(quantitative value) corresponding to the peak area value, and displaysthe concentration on the screen of the display 53.

As is apparent from FIG. 2, if the number of channels is the same, asthe dwell time Td becomes shorter, the loop time TL becomes shorter. Asthe loop time TL becomes shorter, the number of measurement points forthe same channel becomes larger in a given unit time, and the number ofmeasurement points per peak on a mass chromatogram becomes larger, sothat measurement reproducibility is enhanced. That is, if the dwell timeTd is short, even if the time for which a given compound is introducedinto the mass spectrometer 20 is short, namely, even if the linear speedof the mobile phase in the liquid chromatograph unit 10 is high, theaccuracy of a peak area value on a mass chromatogram can be enhanced,and high quantitative accuracy can be secured.

However, if the dwell time Td is short, the following problem occurs.FIG. 5 is a diagram showing actual measurement results of an ionintensity response time of ions originating from reserpine in the casewhere the supply pressure of the CID gas supplied to the collision cell31 is changed in two (high and low) stages. Under the high gas pressure,the rising of the ion intensity is slower than under the low gaspressure, and the response time until the ion intensity becomessubstantially constant is significantly long. This is for the followingreason: if the CID gas pressure inside the collision cell 31 is high, adecrease in ion speed due to contact with the CID gas becomesremarkable, and the time delay until ions finally reach the ion detector34 thus becomes larger.

FIG. 6 is a diagram showing actual measurement results of a relationbetween the dwell time and the signal intensity accumulated value ofreserpine ions in the case where the CID gas pressure is changed in two(high and low) stages. Under the high gas pressure, the CID efficiencyis higher and the number of produced product ions is larger than underthe low gas pressure. Hence, the signal intensity itself as a whole ishigher. However, as the dwell time becomes shorter, a decrease in signalintensity becomes more remarkable. This is for the following reason: inthe case where the CID gas pressure is high, the ion intensity responsetime is long as shown in FIG. 5, and hence, if the dwell time is set tobe short, the slow rising of the ion intensity has relatively largeinfluences. In comparison, in the case where the CID gas pressure islow, the ion intensity response time is short, and hence, even if thedwell time is set to be short, a decrease in signal intensityaccumulated value is small.

In view of the above, in the LC/MS/MS of the present embodiment, thedwell time during which the data collector 41 accumulates pulse signalsis changed in accordance with the CID gas pressure inside the collisioncell 31 (actually, the supply pressure or the supply flow rate of theCID gas supplied into the collision cell 31). Specifically, in the casewhere the CID gas pressure is low, the dwell time is set to be shorterthan in the case where the CID gas pressure is high. In order to performsuch control, an appropriate dwell time value may be empiricallyobtained in advance by, for example, a mass spectrometer manufacturerfor each of the CID gas pressures in the plurality of stages, and may bestored as a dwell time calculation table 51 a shown in FIG. 1 into aprocessing condition parameter memory 51. In the example shown in FIG.1, the CID gas pressure is divided into three stages of less than P1, P1or more and less than P2, and P2 or more, and appropriate dwell timevalues t1, t2, and t3 are respectively associated with the three stages.The number of divisions of the CID gas pressure may be arbitrarilydetermined, and the dwell time may be calculated in not a table form butanother form such as a calculation expression.

In the LC/MS/MS of the present embodiment, if an operator gives aninstruction to execute the MRM measurement mode from the input unit 52and inputs and sets a variety of parameters (for example, themass-to-charge-ratios of precursor ions and product ions at eachchannel) necessary for this measurement mode, the controller 50 obtainsthe dwell time Td corresponding to the current CID gas pressure in theexecuted MRM measurement mode, based on the dwell time calculation table51 a stored in the processing condition parameter memory 51. Then, foreach channel, the controller 50 controls the data collector 41 toaccumulate pulse signals from the ion detector 34 during the obtaineddwell time Td and convert the accumulation result into data.

FIG. 3A and FIG. 3B are schematic waveform diagrams for describing anexample data collecting operation in the case where the dwell time Td ischanged as described above. As shown in FIG. 3B, under the high CID gaspressure, the rising of the ion intensity is slower and the dwell timeTd is longer than under the low CID gas pressure. Hence, the countingtime in the state where the ion intensity is sufficiently risen andstable is long, and the influences of the slow rising are relativelyreduced. As a result, even under the high CID gas pressure, the accuracyand sensitivity of each piece of signal intensity data is enhanced. Inthis case, however, if the number of channels is large, the loop time islong, and hence it is desirable to: reduce the linear speed of themobile phase in the liquid chromatograph unit 10 and thus lengthen theperiod during which one compound is introduced into the massspectrometer 20; or reduce the number of channels, namely, reduce thenumber of compounds measured simultaneously in parallel.

As shown in FIG. 3A, in the case where the CID gas pressure is low andwhere the rising of the ion intensity is rapid, the dwell time Td isshort. Hence, if the number of channels is the same, the loop time canbe shortened. Consequently, the measurement can be finished in a shorttime by increasing the linear speed of the mobile phase in the liquidchromatograph unit 10. Otherwise, a large number of compounds can bemeasured simultaneously in parallel by increasing the number ofchannels.

In the above description, the dwell time Td is changed in accordancewith the CID gas pressure (actually, the supply pressure or the supplyflow rate) inside the collision cell 31. Instead of changing the dwelltime Td, the settling time Ts may be changed. FIG. 4A and FIG. 4B areschematic waveform diagrams for describing an example data collectingoperation in the case where the settling time Ts is changed. As shown inFIG. 4B, if the settling time Ts is lengthened, part of a portion inwhich the ion intensity slowly rises, which is included in part of thedwell time Td in the case where the settling time Ts is short, isincluded in the settling time Ts, and is excluded from the dwell timeTd. As a result, even if the length itself of the dwell time Td isconstant, the proportion of the counting time in the state where the ionintensity is sufficiently risen and stable is increased, and theinfluences of the slow rising are relatively reduced. As a result, evenunder the high CID gas pressure, the accuracy and sensitivity of eachpiece of signal intensity data is enhanced.

Next, a second embodiment of the LC/MS/MS including the tandemquadrupole mass spectrometer according to the present invention isdescribed with reference to the attached drawings. FIG. 7 is aconfiguration diagram of a main part of the LC/MS/MS of the secondembodiment, in which components that are the same as or equivalent tothose in the configuration diagram of the main part of the LC/MS/MS ofthe first embodiment shown in FIG. 1 are denoted by the same referencesigns, and detailed description thereof is omitted. In the LC/MS/MS ofthe second embodiment, the processing condition parameter memory 51 ofthe controller 50 stores an optimum CID gas pressure calculation table51 b showing a correspondence relation between a measurement mode and aCID gas pressure.

A “Q1 scan mode” in the optimum CID gas pressure calculation table 51 bis a measurement mode in which, in the LC/MS/MS, the front-stagequadrupole mass filter 30 performs a mass scan and ions are dissociatedthrough CID inside the collision cell 31. Specifically, the “Q1 scanmode” includes a precursor ion scan measurement mode, a neutral lossscan measurement mode, and a measurement mode in which: precursor ionsthat are selected through the mass scan by the front-stage quadrupolemass filter 30 are dissociated inside the collision cell 31; and theproduced product ions are detected by the ion detector 34 without beingmass-separated. The “MRM measurement mode” includes two types of ahigh-speed mode and a high-sensitivity mode. “Others” includemeasurement modes other than the above-mentioned measurement modes, forexample, a product ion scan measurement mode and a measurement mode inwhich: all ions that pass through the front-stage quadrupole mass filter30 intact are dissociated inside the collision cell 31; specific ionsamong the produced product ions are selected by the rear-stagequadrupole mass filter 33; and the selected ions are detected by the iondetector 34.

The optimum CID gas pressure calculation table 51 b stores apredetermined CID gas pressure (or a predetermined CID gas supplypressure or supply flow rate) for each of the Q1 scan mode, thehigh-speed mode of the MRM measurement, the high-sensitivity mode of theMRM measurement mode, and the other measurement modes. Values of theoptimum CID gas pressure and the like can be appropriately determined bythe mass spectrometer manufacturer. Basically, P4 is less than P5, P6,and P7, and P5 is less than P6.

In the LC/MS/MS of the present embodiment, if the operator designates ameasurement mode to be executed from the input unit 52 and inputs andsets a variety of parameters necessary for this measurement mode, thecontroller 50 obtains a CID gas pressure corresponding to themeasurement mode to be executed at this time, based on the optimum CIDgas pressure calculation table 51 b stored in the processing conditionparameter memory 51. For example, in the case of the precursor ion scanmeasurement mode, the controller 50 derives P4 as the CID gas pressure.Then, when a measurement in the precursor ion scan measurement mode isperformed, the controller 50 controls the CID gas supplier 35 to adjustthe supply pressure or the supply flow rate such that the CID gaspressure inside the collision cell 31 is substantially equal to P4.

Because P4 is normally less than P5, P6, and P7 as described above, inthe case where the precursor ion scan measurement mode and the neutralloss scan measurement mode are executed, the CID gas pressure inside thecollision cell 31 is lower than in the case where other measurementmodes are executed. Hence, although the CID efficiency inside thecollision cell 31 becomes lower, a decrease in ion speed inside thecollision cell 31 is suppressed to be small, and product ions reach theion detector 34 with a relatively small time delay. When the graphcreator 43 creates a mass spectrum, because the ion time delay issuppressed to be relatively small as described above, amass-to-charge-ratio deviation can be small on the created massspectrum.

Moreover, for example, if the high-speed mode of the MRM measurementmode is designated, the controller 50 derives P5 as the CID gaspressure, based on the optimum CID gas pressure calculation table 51 bstored in the processing condition parameter memory 51. When thismeasurement mode is executed, the controller 50 controls the CID gassupplier 35 to adjust the supply pressure or the supply flow rate suchthat the CID gas pressure inside the collision cell 31 is substantiallyequal to P5. Because P5 is normally less than P6 as described above, inthe case where the high-speed mode is executed, the CID gas pressureinside the collision cell 31 is lower than in the case where thehigh-sensitivity mode of the same MRM measurement mode is executed.Hence, although the CID efficiency inside the collision cell 31 becomeslower, ions pass through the inside of the collision cell 31 in arelatively short time, and are introduced into the rear-stage quadrupolemass filter 33. Consequently, even if the time allotted to detectproduct ions originating from a given compound is short, the productions produced from precursor ions originating from the given targetcompound can be detected by the ion detector 34 within the allottedtime. As a result, even in the high-speed mode having lower sensitivity,the ion intensity of the target compound can be reliably obtained.

Because all the above-mentioned embodiments are given as mere examplesof the present invention, even if the embodiments are appropriatelychanged, added, or modified within the range of the gist of the presentinvention, the embodiments are obviously encompassed in the scope ofclaims of the present application.

REFERENCE SIGNS LIST

-   10 . . . Liquid Chromatograph Unit-   11 . . . Mobile Phase Container-   12 . . . Pump-   13 . . . Injector-   14 . . . Column-   20 . . . Mass Spectrometer-   21 . . . Ionization Chamber-   22, 23 . . . Intermediate Vacuum Chamber-   24 . . . Analysis Chamber-   25 . . . Electrospray Ionization Probe-   26 . . . Heated Capillary-   27 . . . Ion Guide-   28 . . . Skimmer-   29 . . . Ion Guide-   30 . . . Front-Stage Quadrupole Mass Filter-   31 . . . Collision Cell-   32 . . . Multi-Pole Ion Guide-   33 . . . Rear-Stage Quadrupole Mass Filter-   34 . . . Ion Detector-   35 . . . CID Gas Supplier-   36 . . . Power Source-   40 . . . Data Processor-   41 . . . Data Collector-   42 . . . Data Memory-   43 . . . Graph Creator-   44 . . . Quantitative Analyzer-   50 . . . Controller-   51 . . . Processing Condition Parameter Memory-   51 a . . . Dwell Time Calculation Table-   51 b . . . Optimum CID Gas Pressure Calculation Table-   52 . . . Input Unit-   53 . . . Display

The invention claimed is:
 1. A tandem quadrupole mass spectrometercomprising: a front-stage quadrupole mass filter for selecting, asprecursor ions, ions having a specific mass-to-charge-ratio from among avariety of ions; a collision cell for causing the precursor ions tocollide with a predetermined gas to dissociate the ions; a rear-stagequadrupole mass filter for selecting ions having a specificmass-to-charge-ratio from among a variety of product ions producedthrough the dissociation; and a detector for detecting the selectedproduct ions, the tandem quadrupole mass spectrometer furthercomprising: a) a gas adjuster for adjusting a supply pressure or asupply flow rate of a gas supplied to an inside of the collision cellsuch that a gas pressure inside the collision cell is in a desiredstate; and b) a controller for changing a length of a dwell time inaccordance with the gas supply pressure or the gas supply flow rate setby the gas adjuster or a target gas pressure when a measurement in amultiple reaction monitoring measurement mode is performed, the dwelltime being a period of time to take in signals obtained by the detectorwith regard to precursor ions and product ions originating from onecompound.
 2. The tandem quadrupole mass spectrometer according to claim1, wherein the controller lengthens the dwell time in a case where thegas pressure inside the collision cell is high, compared with a casewhere the gas pressure inside the collision cell is not high.
 3. Atandem quadrupole mass spectrometer comprising: a front-stage quadrupolemass filter for selecting, as precursor ions, ions having a specificmass-to-charge-ratio from among a variety of ions; a collision cell forcausing the precursor ions to collide with a predetermined gas todissociate the ions; a rear-stage quadrupole mass filter for selectingions having a specific mass-to-charge-ratio from among a variety ofproduct ions produced through the dissociation; and a detector fordetecting the selected product ions, the tandem quadrupole massspectrometer further comprising: a) a gas adjuster for adjusting asupply pressure or a supply flow rate of a gas supplied to an inside ofthe collision cell such that a gas pressure inside the collision cell isin a desired state; and b) a controller for changing a length of asettling time in accordance with the gas supply pressure or the gassupply flow rate set by the gas adjuster or a target gas pressure when ameasurement in a multiple reaction monitoring (MRM) measurement mode isperformed, the settling time being an allowance time necessary forsettling of a voltage applied to the front-stage and/or rear-stagequadrupole mass filter when the applied voltage is changed in order toperform a measurement with at least one of precursor ions and productions being different, after signals obtained by the detector with regardto precursor ions and product ions originating from one compound aretaken in.
 4. The tandem quadrupole mass spectrometer according to claim3, wherein the controller lengthens the settling time in a case wherethe gas pressure inside the collision cell is high, compared with a casewhere the gas pressure inside the collision cell is not high.